Project Details
Description
Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in Western countries. We discovered that forebrain HSE (via olfactory neurons) in otherwise healthy children can result from inborn errors of the TLR3 pathway (TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3), whereas brainstem HSE (via trigeminal (TG) neurons) can result from inborn errors of RNA lariat metabolism due to bi-allelic mutations in DBR1. We also found that children with a broader defect of impaired production of (mutations in NEMO) or response to IFN-α/β and IFN-λ (STAT1) are prone to HSE and other infections. Thanks to NIH R01NS072381, we analyzed the cellular basis of HSE using induced pluripotent stem cell (iPSC)-based peripheral and central nervous system (CNS) cell differentiation technology. We first showed that forebrain HSE in TLR3 pathway-deficient patients results from impaired anti-HSV1 intrinsic (i.e. non-hematopoietic) immunity in forebrain cortical neurons and pro-oligodendrocytes, whereas astrocytes and neural stem cells were not affected by TLR3 deficiency (microglial cells were not tested). More recently, we showed that iPSC-derived trigeminal (TG) neurons do not rely on TLR3 to control HSV1 (olfactory neurons were not tested). These data indicated that childhood HSE results from inborn errors of non-hematopoietic, CNS-specific, cell-intrinsic immunity, affecting cortical neurons and oligodendrocytes in particular. We have since identified new forebrain HSE-causing genes that are connected to the canonical TLR3-IFN circuit (MEX3B, IFNAR1), to the non-canonical TLR3-necroptosis pathway (RIPK3), or that underlie HSE via other mechanisms (SNORA31, TMEFF1). The goal of this renewal application is to dissect in greater breadth and depth the CNS-specific and -intrinsic pathogenesis of HSE. We will test the hypotheses that (1) the new genetic etiologies of forebrain HSE impair intrinsic immunity in CNS but not olfactory neurons, (2) DBR1 def
Status | Finished |
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Effective start/end date | 4/1/21 → 3/31/23 |
Funding
- Rockefeller University (SUB00000264 AMD 5 // 5R01NS072381-12)
- National Institute of Neurological Disorders and Stroke (SUB00000264 AMD 5 // 5R01NS072381-12)
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